In this study we use a single oral dose of [3′,3′]-D2-nicotine, similar to that used previously by Dempsey et al. [14]to establish the relationship between CYP2A6 genotype and oral nicotine metabolism. Plasma concentrations of nicotine and its metabolites, and nicotine metabolite ratios are used as metrics of CYP2A6 activity. The metabolism of oral nicotine occurs predominantly in the liver and CYP2A6 is the primary hepatic catalyst of nicotine metabolism. Therefore, quantifying the conversion of nicotine to cotinine should allow the direct characterization of the impact of CYP2A6 genotype on nicotine 5′-oxidation. Administration of D2-nicotine and assessment of its metabolism in 189 European Americans, both current smokers and former-smokers, allowed us to confirm the functional significance of some CYP2A6 polymorphisms and redefine others. Relative nicotine metabolism was used to estimate parameters for each haplotype and a robust genetic model of CYP2A6-catalyzed metabolism was developed. This model, defining CYP2A6 genotype as a quantitative measure of enzyme activity, may be further applied to the study of CYP2A6 genotype and smoking behavior.
